The fundamental objective of this research is to develop a new set of immunogenetic tools--monoclonal antibodies to natural killer (NK) cell associated alloantigens and congenic strains of mice for NK-associated genes--for investigating NK cell immunobiology and immunoregulation. NK cell-associated antigens on resting versus activated cells will be biochemically and genetically defined. Antibodies which inhibit or enhance NK cell activity will be selected, and those which block the binding of NK cells to targets or block the lytic activity of NK cells will be used to define cell surface structures active in NK cell functions. The sites of gene action of genes known to influence NK function will be studied, including genes influencing NK development, numbers or binding and activation. Two murine models of NK dysfunction will be studied: SB/Le-beige mice, in which the presence of NK activity is associated with acceleration of autoimmune disease, and SM/J mice, in which certain genes control hyperactivity of NK cells. A comparative study of mouse and human NK cell-associated antigens will be undertaken so that true homologs can be established. Finally, monoclonal antibodies will be used to deplete NK cell activity in vivo to test the effect of NK immunodeficiency on immunocompetence.